Rare Disease 2 —
Training activity: 9

Details

Review referrals; analyse, interpret and report results from Whole Genome Sequencing (WGS) testing to include,

• coding variation
• non-coding variation

Type

Entrustable training activity (ETA)

Evidence requirements

Evidence the activity has been undertaken by the trainee repeatedly, consistently, and effectively over time, in a range of situations. This may include occasions where the trainee has not successfully achieved the outcome of the activity themselves. For example, because it was not appropriate to undertake the task in the circumstances or the trainees recognised their own limitations and sought help or advice to ensure the activity reached an appropriate conclusion. ​

Reflection at multiple timepoints on the trainee learning journey for this activity.

Reflective practice guidance

The guidance below is provided to support reflection at different time points, providing you with questions to aid you to reflect for this training activity. They are provided for guidance and should not be considered as a mandatory checklist. Trainees should not be expected to provide answers to each of the guidance questions listed.

Before action

What does success look like?

• How will you identify what is expected of you in relation to triaging referrals for Whole Genome Sequencing (WGS) compared to standard NGS gene panels?
• What constitutes a successful and thorough analysis of WGS data, specifically regarding the identification and prioritisation of both coding and non-coding variation?
• How will you demonstrate proficiency in using bioinformatic tools and best practice guidelines to investigate the clinical significance of variants found in non-coding or regulatory regions?
• What are the standards for a high-quality WGS interpretive report that ensures management recommendations are clear, safe, and actionable for the patient?
• What steps have you planned to gain clarity on the expected depth of non-coding analysis and local reporting templates?

What is your prior experience of this activity?

• Think about what you already know about WGS bioinformatic pipelines and how your experience with NGS panels or exome analysis provides a foundation for this activity.
• Consider possible challenges you might face, such as managing the vast scale of WGS data, filtering out benign non-coding variation, or interpreting variants in genomic regions with complex regulatory elements.
• How do you recognise the scope of your own practice? In what situations—such as encountering a novel non-coding variant or a potential incidental finding—will you need to seek advice from a senior Clinical Scientist or Clinical Geneticist?
• How are you feeling about embarking on the detailed interpretation and reporting of WGS data, given the potential for identifying complex or unexpected results that impact the patient and their family?

What do you anticipate you will learn from the experience?

• What specific analytical skills do you want to develop, such as refining your ability to use splice prediction tools or conservation scores to assess the impact of intronic variants?
• Identify the specific insights you hope to gain regarding the clinical utility of WGS in identifying causative variation that may have been missed by previous targeted or panel-based testing.
• In what ways do you anticipate this experience will improve your ability to communicate complex genomic findings, particularly in explaining the clinical relevance of non-coding variants to multidisciplinary colleagues?

What additional considerations do you need to make?

• How will you consult actions identified following previous experiences of variant interpretation or NGS analysis to ensure you are building upon earlier feedback regarding data filtering and prioritisation?
• Which specific clinical and technical resources—including National Genomic Test Directory eligibility for rare diseases, the functional significance of non-coding genomic elements, and local policies for reporting incidental findings—have you reviewed to ensure your approach to Whole Genome Sequencing interpretation is evidence-based and safe?
• What steps have you planned to ensure clarity on the limits of your responsibility when resolving complex interpretative or technical issues in the WGS workflow?

In action

What does success look like?

• How will you identify what is expected of you in relation to triaging referrals for Whole Genome Sequencing (WGS) compared to standard NGS gene panels?
• What constitutes a successful and thorough analysis of WGS data, specifically regarding the identification and prioritisation of both coding and non-coding variation?
• How will you demonstrate proficiency in using bioinformatic tools and best practice guidelines to investigate the clinical significance of variants found in non-coding or regulatory regions?
• What are the standards for a high-quality WGS interpretive report that ensures management recommendations are clear, safe, and actionable for the patient?
• What steps have you planned to gain clarity on the expected depth of non-coding analysis and local reporting templates?

What is your prior experience of this activity?

• Think about what you already know about WGS bioinformatic pipelines and how your experience with NGS panels or exome analysis provides a foundation for this activity.
• Consider possible challenges you might face, such as managing the vast scale of WGS data, filtering out benign non-coding variation, or interpreting variants in genomic regions with complex regulatory elements.
• How do you recognise the scope of your own practice? In what situations—such as encountering a novel non-coding variant or a potential incidental finding—will you need to seek advice from a senior Clinical Scientist or Clinical Geneticist?
• How are you feeling about embarking on the detailed interpretation and reporting of WGS data, given the potential for identifying complex or unexpected results that impact the patient and their family?

What do you anticipate you will learn from the experience?

• What specific analytical skills do you want to develop, such as refining your ability to use splice prediction tools or conservation scores to assess the impact of intronic variants?
• Identify the specific insights you hope to gain regarding the clinical utility of WGS in identifying causative variation that may have been missed by previous targeted or panel-based testing.
• In what ways do you anticipate this experience will improve your ability to communicate complex genomic findings, particularly in explaining the clinical relevance of non-coding variants to multidisciplinary colleagues?

What additional considerations do you need to make?

• How will you consult actions identified following previous experiences of variant interpretation or NGS analysis to ensure you are building upon earlier feedback regarding data filtering and prioritisation?
• Which specific clinical and technical resources—including National Genomic Test Directory eligibility for rare diseases, the functional significance of non-coding genomic elements, and local policies for reporting incidental findings—have you reviewed to ensure your approach to Whole Genome Sequencing interpretation is evidence-based and safe?
• What steps have you planned to ensure clarity on the limits of your responsibility when resolving complex interpretative or technical issues in the WGS workflow?

On action

What happened?

• How would you summarise the key points of the WGS cases you reviewed, specifically regarding the types of coding and non-coding variations identified?
• What specific technical or clinical details felt most important during the process, such as navigating the WGS bioinformatic pipeline or applying filtering strategies to manage the vast volume of data?
• Which ‘reflect-in-action’ moments did you notice where you had to adapt as the situation unfolded—for example, by adjusting your variant prioritisation parameters upon identifying a novel regulatory variant?
• How did you feel during the experience, particularly when handling the professional responsibility of interpreting high-complexity data that includes non-coding regions with potentially significant clinical implications for the patient?

How has this experience contributed to your developing practice?

• What specific learning can you take from this experience regarding the employment of specialist knowledge to distinguish between pathogenic non-coding variants and benign genomic background?
• How did this experience improve your proficiency in performing whole genome analysis and using bioinformatic tools to investigate the clinical significance of variants in regulatory regions?
• What strengths did you demonstrate (e.g., efficient data filtering) and what knowledge gaps were evident (e.g., a need for deeper understanding of deep intronic splice-site predictions)?
• How does this WGS activity compare against your previous experiences with NGS gene panels or exome analysis—were any previously identified actions for development achieved?
• Identify any challenges you experienced, such as managing conflicting bioinformatic scores for non-coding variants, and how you reacted to them—did you successfully overcome these to ensure a safe and high-quality service?
• Did you need to seek advice or escalate a complex WGS profile to a senior Clinical Scientist or bioinformatician to ensure you were working strictly within your professional scope of practice?
• How does mastering WGS interpretation relate to the requirements for your future post-programme practice as a Clinical Scientist?

What will you take from the experience moving forward?

• What specific actions will you now take to support the assimilation of what you have learned, such as reviewing national guidelines for the reporting of non-coding variation?
• What will you do differently next time you analyse a WGS case? Has anything changed in terms of how you would approach the triage of referrals or the validation of secondary findings?
• Do you need to practise any aspect of the activity further, such as refining your use of splice prediction software or gaining more experience with structural variant calling in WGS data?
• What support or resources (e.g., expert mentorship in bioinformatics, access to specialised non-coding variant databases, or further attendance at variant interpretation meetings) have you identified as necessary for your ongoing development?

Beyond action

Have you revisited the experiences?

• How have you evaluated and re-evaluated your initial bioinformatic filtering strategies for non-coding variation in light of your subsequent experience with a broader range of WGS clinical indications?
• Have you reviewed your actions from previous reflections for this activity to determine if you have completed identified tasks, such as mastering specific splice prediction tools or reviewing local policies on secondary findings?
• When performing a module review, what overarching themes or learning patterns have you identified regarding your ability to justify the clinical significance of variants in regulatory regions versus coding regions?
• In what ways has discussions with senior clinical scientists or bioinformaticians regarding complex WGS cases led to a transformation in your approach to manual variant adjudication?
• Are you now ready to demonstrate this new learning in practice when navigating the complexities of whole genome data for increasingly vague rare disease phenotypes?

How have these experiences impacted upon current practice?

• How has the accumulated learning from interpreting vast WGS datasets supported your preparation for observed ‘in-person’ assessments, such as a Case-based Discussion (CBD) on rare disease pathways or a DOPS titled ‘Classify a variant’?
• How has your practice in filtering and prioritising variants developed and evolved over time, and can you identify instances where you are now more efficient at distinguishing pathogenic non-coding variants from genomic background?
• In what ways are you now more confident in recognising the limits of your own professional scope of practice when encountering novel regulatory findings that require senior specialist review?
• What transferable skills in clinical reasoning and technical problem-solving have you developed that will allow you to evaluate and adopt new genomic technologies or lead service improvement projects in the future?
• How have these experiences shaped your professional identity and reinforced your commitment to a patient-centred approach when reporting complex results that have significant implications for a family?
• How will your current mastery of WGS interpretation help you contribute to future innovations and the integration of new testing algorithms within the clinical genomics service?

Relevant learning outcomes

#	Outcome
# 1	Outcome Review referrals for patients referred for rare disease genomic testing.
# 2	Outcome Analyse, interpret and report results for diagnostic, presymptomatic and familial/carrier rare disease genomic testing.
# 3	Outcome Perform targeted analysis, whole genome analysis, and chromosomal analysis for patients referred for rare disease genomic testing.
# 4	Outcome Interpret genomic variants to investigate their clinical significance for patients referred for rare disease genomic testing.
# 7	Outcome Employ specialist knowledge of rare disease genomic testing to deliver a safe and high-quality service.
# 8	Outcome Demonstrate appropriate communication skills with healthcare professional colleagues to inform the clinical management of patients referred for rare disease genomic testing.